Search

Abstract Purpose We aimed at analysing the risk of congestive heart failure (CHF) among first‐ and second‐generation immigrants in younger age groups. Methods All individuals aged 18–54 years, n = 3 973 454 in the first‐generation study and n = 3 817 560 in the second‐generation study, were included. CHF was defined as at least one registered diagnosis in the National Patient Register between 1 January 1998 and 31 December 2018. Cox regression analysis was used to estimate the relative risk [hazard ratios (HRs) with 99% confidence intervals (CIs)] of incident CHF with adjustments for age, co‐morbidities and socio‐demographics. Results In the first‐generation study, a total of 85 719 cases of CHF were registered, 54 369 men and 31 350 women, where fully adjusted models showed HRs for all foreign‐born men of 1.12 (99% CI 1.06–1.17) and for women of 0.99 (0.92–1.05). Groups with higher risk included men from Eastern Europe, Central Europe, Africa and Asia and women from Africa and Asia, and a lower risk was found among Latin American women. In the second‐generation study, a total of 88 999 cases of CHF were registered, 58 403 men and 30 596 women, where fully adjusted models showed HRs for second‐generation men of 1.04 (0.99–1.09) and women of 0.97 (0.90–1.04). Conclusions The higher risk in some foreign‐born groups needs to be paid attention to in clinical practice. The fact that almost all increased risks were attenuated and absent in second‐generation immigrants suggests that lifestyle and environmental factors are more important than genetic differences in the risk of CHF.

Abstract Cardiovascular-kidney-metabolic health reflects the interactions between metabolic risk factors, chronic kidney disease, and the cardiovascular system. A growing body of literature suggests that metabolic syndrome (MetS) in individuals of normal weight is associated with a high prevalence of cardiovascular diseases and an increased mortality. The aim of this study was to establish a non-invasive preclinical model of MetS in support of future research focusing on the effects of novel antidiabetic therapies beyond glucose reduction, independent of obesity. Eighteen healthy adult Beagle dogs were fed an isocaloric Western diet (WD) for ten weeks. Biospecimens were collected at baseline (BAS1) and after ten weeks of WD feeding (BAS2) for measurement of blood pressure (BP), serum chemistry, lipoprotein profiling, blood glucose, glucagon, insulin secretion, NT-proBNP, angiotensins, oxidative stress biomarkers, serum, urine, and fecal metabolomics. Differences between BAS1 and BAS2 were analyzed using non-parametric Wilcoxon signed-rank testing. The isocaloric WD model induced significant variations in several markers of MetS, including elevated BP, increased glucose concentrations, and reduced HDL-cholesterol. It also caused an increase in circulating NT-proBNP levels, a decrease in serum bicarbonate, and significant changes in general metabolism, lipids, and biogenic amines. Short-term, isocaloric feeding with a WD in dogs replicated key biological features of MetS while also causing low-grade metabolic acidosis and elevating natriuretic peptides. These findings support the use of the WD canine model for studying the metabolic effects of new antidiabetic therapies independent of obesity.

BACKGROUND: Myasthenia gravis (MG) is a rare autoimmune disease affecting neuromuscular junction involvement. The finding that T-reg level in MG patients was lower than that in normal persons leads to the idea that the primary pathology of the disease is T-reg dependent. The T-reg level of MG patients seems to be decreasing compared to that of normal persons. The study was conducted to observe the contribution of T-reg level in plasma injected into Swiss-Webster mice to develop clinically and pathologically myasthenic syndromes. METHODS: Swiss-Webster mice were grouped into three groups: the groups received plasma with normal, low, and high T-reg levels, respectively. The T-reg levels of the mice were measured with flow cytometry analysis and a human regulatory T-cell cocktail for T-cell surface cell marker. The motor function, interleukin (IL)-2, interferon (IFN)-γ, and thymus weight of mice were measured after the injection. Histopathological examination was performed to analyze mice’s muscles and thymus. RESULTS: The result identified that the motor function (2-week treatment group: p=0.021 and 3-week treatment group: p=0.032) and muscle width (p=0.014, p=0.032 and p≤0.001) were significantly lower in the low T-reg level plasma group compared to control and high T-reg level plasma groups. The thymus showed an increase in weight without an increase in the cortex-medulla ratio of the thymus, indicating hyperplasia. Both IL-2 and IFN-γ levels were lower in the low and high T-reg level groups compared with the control group, indicating the autoimmune process. CONCLUSION: Low T-reg level was associated with lower motor function, muscle width, increased thymus weight, as well as lower IL-2 and IFN-γ levels. T-reg level contributed to clinical myasthenic syndromes but not pathological findings. This research method is expected to be a basis for the development of animal models with Swiss-Webster mice. KEYWORDS: animal model, Myasthenia gravis, Swiss-Webster mice

Abstract Background There is increasing evidence implicating hemoglobin/heme and their scavengers in oxidative stress-mediated pathologies, but information is limited in abdominal aortic aneurysm (AAA). Methods and results In this case-control study, we assessed heme/heme-related markers in 142 men with AAA and 279 men with a normal aortic diameter consecutively recruited from an ultrasound screening program in Sweden. Enzyme-linked immunosorbent assays (ELISAs) were used to measure heme oxygenase-1 (HO-1) and hemopexin (Hpx) plasma levels, colorimetric assays for cell-free heme and whole blood hemoglobin (Hb) levels, and droplet digital PCR (ddPCR) and real-time PCR to determine haptoglobin (Hp) (pheno)type and genotype, respectively. Hpx and heme plasma levels at baseline were elevated, while HO-1 levels were lower in men with AAA (p

Purpose: We aimed to analyze the risk of hereditary hemochromatosis (HH) among first-generation and second-generation immigrants in Sweden using Swedish-born individuals and Swedish-born individuals with Swedish-born parents as referents, respectively. Methods: All individuals aged 18 years of age and older, n = 6,180,500 in the first-generation study, and n = 4,589,930 in the second-generation study were included in the analyses. HH was defined as at least one registered diagnosis International Classification of Diseases 10th edition (E83.1) in the National Patient Register between January 1, 1998 and December 31, 2018. Cox regression was used to estimate the hazard ratios (HRs) with 99% confidence intervals (CI) owing to multiple testing, of incident HH with adjustments for age, cancer, other comorbidities, and socio-demographics. Results: In the first-generation study, there were 5,112 cases of HH, and in the second-generation study 4,626 cases of HH. The adjusted HRs for first-generation men and women overall were 0.72 (99% CI: 0.63–0.82) and 0.61 (99% CI: 0.52–0.72), respectively, and for the second-generation men and women 0.72 (99% CI: 0.62–0.83) and 0.97 (99% CI: 0.83–1.14), respectively, with a higher risk found only among first-generation men from Western Europe, HR 1.47 (99% CI: 1.05–2.06), compared to the control group. Conclusions: Our findings indicate that the overall risk of HH was lower among both first-generation and second-generation immigrants when compared to individuals born in Sweden or with Swedish-born parents. An elevated risk for HH was observed exclusively among first-generation men originating from Western Europe. These findings represent new knowledge and should be of global interest.

We aimed to investigate the school performance gap and its potential trend from 2010 to 2020 in non-immigrant and second-generation immigrant children in Sweden, whether parental mental disorders and low socioeconomic status contribute to this gap and its trends, and whether the effects of these factors differ by immigration status. We used multiple Swedish population registers, including 829,787 children born 1994–2004. We examined the school performance gap and its trends by the interaction between immigration status and year with linear mixed models. We assessed whether parental mental disorders and socioeconomic status contributed to this gap and its trends, and whether their effects on school performance differ by immigration status. The existing gap was explained by parental mental disorders in addition to parental education and neighborhood socioeconomic status for both males and females. The unadjusted model suggested an increasing trend of the existing gap in school performance by immigration status for both males and females. In the adjusted model, the increasing trend of the gap remained among males and was partially attributed to parental education and neighborhood socioeconomic status. The interaction tests showed that the potential effects of these factors on school performance were smaller among second-generation immigrant children. Efforts to reduce the effects of socioeconomic inequalities and parental mental disorders are warranted in addition to extra support for second-generation immigrant children at schools.

Objective: Information on how parental risk for posttraumatic stress disorder (PTSD) relates to their children’s risk for drug use disorder (DUD) and alcohol use disorder (AUD) is limited. This study is the first to utilize an extended adoption design which can address questions about the degree of, and sources of, cross-generational and cross-disorder transmission of PTSD and substance use disorders.Method: We examined diagnoses using Swedish National registries for parents and their adult offspring (n = 2,194,171, born 1960–1992) from six types of families (intact (1), not lived with biological father (2) or mother (3), step father (4), step mother (5), and adoptive (6)). Parent–child resemblance was assessed by tetrachoric correlation.Results: PTSD and DUD showed an approximately symmetrical cross-generational cross-disorder relationship. Conversely, AUD in parents was more related to the risk for PTSD in offspring compared to the reverse direction. The cross-disorder cross-generation transmission correlations for PTSD to DUD were higher than those for PTSD to AUD. Genetic and rearing correlations for PTSD-DUD were estimated at + .79 (CI: .66, .91) and + .49 (CI: .33, .65), significantly higher than those for PTSD-AUD + .59 (CI: .48, .71) and + .28 (CI: .12, .44).Conclusions: PTSD and the substance use disorders demonstrated cross-transmission, but more so for DUD. PTSD and DUD demonstrated highly correlated genetic effects, and moderately correlated rearing effects. Correlations of genetic and rearing effects between PTSD and AUD were lower than those for PTSD and DUD.

ABSTRACTWomen are at significantly greater risk of metabolic dysfunction after menopause, which subsequently leads to numerous chronic illnesses. The gut microbiome is associated with obesity and metabolic dysfunction, but its interaction with female sex hormone status and the resulting impact on host metabolism remains unclear. Herein, we characterized inflammatory and metabolic phenotypes as well as the gut microbiome associated with ovariectomy and high-fat diet feeding, compared to gonadal intact and low-fat diet controls. We then performed fecal microbiota transplantation (FMT) using gnotobiotic mice to identify the impact of ovariectomy-associated gut microbiome on inflammatory and metabolic outcomes. We demonstrated that ovariectomy led to greater gastrointestinal permeability and inflammation of the gut and metabolic organs, and that a high-fat diet exacerbated these phenotypes. Ovariectomy also led to alteration of the gut microbiome, including greater fecal β-glucuronidase activity. However, differential changes in the gut microbiome only occurred when fed a low-fat diet, not the high-fat diet. Gnotobiotic mice that received the gut microbiome from ovariectomized mice fed the low-fat diet had greater weight gain and hepatic gene expression related to metabolic dysfunction and inflammation than those that received intact sham control-associated microbiome. These results indicate that the gut microbiome responds to alterations in female sex hormone status and contributes to metabolic dysfunction. Identifying and developing gut microbiome-targeted modulators to regulate sex hormones may be useful therapeutically in remediating menopause-related diseases.

Background Lymphatic disorders such as protein‐losing enteropathy, plastic bronchitis, and chylothorax are important complications of the Fontan circulation and ultimately result in an increased risk of early death. Several European centers are now performing lymphatic procedures. The aim of this study is to map the extent of these lymphatic disorders and treatments provided across European pediatric cardiology centers. Methods and Results A survey was circulated to 49 European pediatric cardiology centers consisting of 37 questions including a mix of binary, categorical, and continuous variables. Thirty‐one centers (63%) participated in the study, performing a median of 250 (interquartile range, 178 ‐ 313) cardiopulmonary bypass procedures per year. Chylothorax emerged as the most prevalent lymphatic disorder followed by protein‐losing enteropathy and plastic bronchitis. The most common diagnostic investigation method was noncontrast magnetic resonance lymphangiography (52%). Eleven centers (35%) conducted lymphatic interventions with a median of 3 (interquartile range, 1 ‐ 4) procedures per year and 12 (interquartile range, 5 ‐ 15) interventions in total per center. Conclusions This study confirms the rarity of and variation in treatment approaches for lymphatic disorders across Europe. With at least 11 centers offering lymphatic interventions, the adoption of these procedures is on the rise in Europe. To improve the quality of care and treatment outcomes for these complex patients, it is crucial to consider evidence‐based lymphatic diagnostics, interventional lymphatic procedures, and the centralization of services in Europe.

Background: Mitochondrial DNA copy number (mtDNA-CN) is associated with aging. A relationship between mtDNA-CN and degenerative disorders, e.g. osteoarthritis (OA) and osteoporosis (OP), has been suggested. We aimed to investigate the relationship of mtDNA-CN and incident OA and OP. Materials and methods: MtDNA-CN was studied in relationship to incident OA and OP in a population-based cohort study of 6916 middle-aged women (52–63 years). Totally 2521 women with sufficient quality of mtDNA were analyzed. After exclusions, 1978 women remained in the study population. Four different endpoints obtained from the National Patient register were studied: 1) OA, 2) OP 3) OA surgery, and 4) OP fracture. In the multivariate model adjustments were made for potential OA and OP risk factors. Results: Women with low mtDNA-CN were older and had more activity at work. 125 women (6.32%) were affected by incident OP and 254 women (12.84%) had an OP fracture. Incident OA affected 451 women (22.80%) and 175 women (8.85%) had OA surgery. There were no associations between mtDNA-CN and incident risk of OA (Hazard ratio ​= ​1.00, 95% confidence interval 0.83–1.20), OA surgery (0.79, 0.58–1.07), OP (0.89, 0.62–1.27), or OP fracture (1.00, 0.78–1.29). However, incident OP was significantly associated with T-score (bone density), smoking, diabetes mellitus, and chronic obstructive bronchitis (COPD). OA was associated with body mass index and COPD. Conclusions: The present study suggests that mtDNA-CN, reflecting mitochondrial dysfunction, is not a major predictor for incident OA or OP. However, due to the limited study size minor associations cannot be excluded.

Abstract Many ecosystems are defined and shaped by one or a few common, foundation species. Even though such species hold a key role in the restoration of these ecosystems, the demographic processes involved in their re‐establishment have rarely been studied. Foundation species' population dynamics, re‐establishment history, and the abiotic and biotic factors that affect individual establishment at restored sites can be studied by addressing population spatial patterns and age structure. Such an approach to studying population dynamics is particularly relevant for long‐lived species with low mortality, such as shrubs in alpine areas. We studied a population of the foundation species Empetrum nigrum ssp. hermaphroditum at an alpine spoil heap site and found evidence of population re‐establishment starting within a decade after construction. High Empetrum densities close to the spoil heap edges indicated that short distances to seed sources in the surroundings had a strong positive effect on establishment of individuals. Empetrum individuals were significantly clustered, which indicated intraspecific facilitation. As revealed by spatial analyses of recruits and older, established individuals, clustering developed gradually over time, which indicated a shift from no interaction to increased facilitation. We conclude that intraspecific facilitation promotes Empetrum reestablishment at the studied alpine spoil heap. Synthesis: We show that population spatial patterns and age structure can be successfully used to unveil the re‐establishment history of a foundation species in a restoration context. Efficient seed dispersal and intraspecific facilitation seem to be important factors behind Empetrum's successful re‐establishment at alpine spoil heaps. Identification of abiotic and biotic factors determining foundation species' establishment success at restored sites can support planning and improve success of restoration.

There has been an increased concern on indoor air quality (IAQ) in residences since the majority of individuals’ time is mainly spent indoors. We inspected and measured indoor environmental parameters in 399 homes in northeast China in order to study IAQ. We systematically measured multilevel environmental parameters (physical, chemical, and biological) in children’s bedrooms during all seasons. The results indicated that the median values for indoor temperature, relative humidity, total volatile organic compounds (TVOC), and formaldehyde concentrations throughout the year were within the Chinese national standards. However, the median carbon dioxide concentrations exceeded 1000 ppm during spring, autumn, and winter. In the same seasons, the air change rate (ACR) was below the minimum required level of 0.5 h−1. Di-2-ethylhexyl phthalate (DEHP), di-n-butyl phthalate (DnBP), and di-isobutyl phthalate (DiBP) were predominantly detected in settled dust, displaying median concentrations of 126.9, 41.5, and 16.3 μg/g, respectively. Notably, phthalate concentrations were significantly higher in urban houses as compared to rural houses. Furthermore, median concentrations of Dermatophagoides farinae (Der f) and endotoxin were 689.4 ng/g and 3689.1 EU/g, respectively, trending higher in winter than summer. There was a negative correlation between ACR and chemical pollutants (TVOC, formaldehyde, and DiBP). In conclusion, northeast Chinese homes had poor indoor air quality with ubiquitous exposure to modern chemical compounds and insufficient ventilation.

The gut and the gut microbiome communicate with the nervous system through the gut–brain axis via neuroimmune and neuroendocrine mechanisms. Despite existing research, studies exploring this link in aging dogs are limited. This study aims to examine multiple blood and fecal biomarkers of intestinal health, along with various behavioral indicators based on saliva, blood, observations, and activity, in different age populations (junior: 7 y.o.) of thirty-seven Beagle dogs. In our study, Bacteroides were significantly higher in senior dogs. The relative abundance of Faecalibacterium and Blautia showed age-related trends, higher in senior and junior dogs, respectively. Fecal short-chain fatty acid concentration, especially acetate, increased with age, while propionate was higher in junior dogs. For the behavioral indicators we considered, blood thyroxine concentration, playing, exploring, and total activity were higher in junior dogs. The differences observed between the biomarkers of gut health and behavior, particularly those significant for the age correlations, emphasize the importance of considering age-related factors when studying the gut microbiome and behavior. However, further research is needed to better understand the mechanisms and specific pathways involved in the relationship between the studied biomarkers and age.

Several recent studies have evaluated technologies of spent nuclear fuel processing specifically for solidifying transuranic (TRU) waste as a by-product of fission. Of the TRU group, plutonium and the minor actinides will be responsible for the bulk of the radiotoxicity and heat generation of spent nuclear fuel in the long term (300 to 20,000 years). In this study, we investigated magnesium potassium phosphate (MKP)-based compounds as host waste forms for the encapsulation of inactive trivalent Nd and Sm as analogues of the minor trivalent actinides, Am and Cm. Waste forms were fabricated under ambient atmospheric conditions by adding 5 wt.% of substances containing Nd or Sm via the following two routes: powder oxides and aqueous solutions of nitrate salts. Waste form performance was established using strength and aqueous medium leaching tests of MKP-based specimens. The MKP materials were analyzed by X-ray diffraction (XRD), scanning and transmission electron microscopy (SEM and TEM), energy-dispersive X-ray spectroscopy (EDS), and Raman spectroscopy. The waste forms exhibited a compressive strength of ≥30 MPa and were durable in an aqueous environment. The leachability indices for Nd and Sm, as per the ANS 16.1 procedure, were 19.55–19.78 and 19.74–19.89, respectively, which satisfy the acceptable criteria (>6). The results of the present room temperature leaching study suggest that MKPs can be effectively used as a host material to immobilize actinides (Am and Cm) contained in TRU waste.

Air pollution monitoring in industrial regions like Moravia-Silesia faces challenges due to complex environmental conditions. Low-cost sensors offer a promising, cost-effective alternative for supplementing data from regulatory-grade air quality monitoring stations. This study evaluates the accuracy and reliability of a prototype node containing low-cost sensors for carbon monoxide (CO) and particulate matter (PM), specifically tailored for the local conditions of the Moravian-Silesian Region during winter and spring periods. An analysis of the reference data observed during the winter evaluation period showed a strong positive correlation between PM, CO, and NO2 concentrations, attributable to common pollution sources under low ambient temperature conditions and increased local heating activity. The Sensirion SPS30 sensor exhibited high linearity during the winter period but showed a systematic positive bias in PM10 readings during Polish smog episodes, likely due to fine particles from domestic heating. Conversely, during Saharan dust storm episodes, the sensor showed a negative bias, underestimating PM10 levels due to the prevalence of coarse particles. Calibration adjustments, based on the PM1/PM10 ratio derived from Alphasense OPC-N3 data, were initially explored to reduce these biases. For the first time, this study quantifies the influence of particle size distribution on the SPS30 sensor’s response during smog episodes of varying origin, under the given local and seasonal conditions. In addition to sensor evaluation, we analyzed the potential use of data from the Copernicus Atmospheric Monitoring Service (CAMS) as an alternative to increasing sensor complexity. Our findings suggest that, with appropriate calibration, selected low-cost sensors can provide reliable data for monitoring air pollution episodes in the Moravian-Silesian Region and may also be used for future adjustments of CAMS model predictions.

Tree species’ ability to persist within their current distribution ranges is determined by seed germination and seedling growth. Exploring variation in these traits in relation to climatic conditions helps to understand and predict tree population dynamics, and to support species management and conservation under future climate. We analyzed seeds and seedlings of 26 European beech populations from the northeastern boundary of the species range to test whether: 1) adaptation to climatic conditions is reflected in depth of dormancy and germination of seeds; 2) climatic characteristics of origin predictably affect seedling traits. The variation in seed dormancy and germination in a laboratory test, and seedling growth and morphology traits in a nursery common-garden test was examined. Populations originating from warmer and drier sites (mostly from the northern region), compared to those from the opposite end of climatic gradient, germinated later, with a lower success, and produced seedlings with shorter and tougher roots. They had deeper dormancy and poorer seed germination capacity, and are likely more vulnerable to environmental changes. The climatic conditions at the origin shape the intraspecific variation of seed germination and seedling traits, and may limit regeneration from seed and affect adaptation potential of beech to increasing temperatures and decreasing precipitation.

Abstract Background Giardia duodenalis (Gd) causes intestinal parasitosis. The involvement of the intestinal microbiome in determining the infection's clinical phenotype is unknown. Objective Investigate the fecal microbiome features in dogs with giardiasis. Animals and Methods Cross‐sectional study, including fecal samples of kenneled dogs with Gd diagnosed by fecal Giardia antigen dot ELISA. The fecal microbial compositional characteristics and dysbiosis index (DI) were compared between diarrheic and nondiarrheic dogs. Results Fecal samples of 38 Gd‐infected dogs (diarrheic, 21; nondiarrheic, 17) were included. No differences were found in Faith's phylogenic diversity and beta diversity (weighted UniFrac distances) and in specific taxa abundances at the phylum, genus, and species levels, as well as in alpha and beta diversities between diarrheic and nondiarrheic dogs, and also when divided by sex or age. Among diarrheic dogs, alpha diversity was higher in males than in females (pairwise Kruskal‐Wallis, q = 0.01). Among males, fecal abundances of the genus Clostridium (W = 19) and Clostridium spiroforme species (W = 33) were higher in diarrheic compared to nondiarrheic dogs. In diarrheic dog fecal samples, Proteobacteria were more prevalent (W = 1), whereas Verrucomicrobia were less prevalent in dogs

Abstract Background Breast cancer is, despite screening, not always detected early enough and is together with other tumor types known to shed genetic information in circulation. Unlike single-copy nuclear DNA, mitochondrial DNA (mtDNA) copies range from 100s to 10,000s per cell, thus providing a potentially alternative to identify potential missing cancer information in circulation at an early stage. Methods To characterize mitochondrial mutation landscapes in breast cancer, whole mtDNA sequencing and bioinformatics analyses were performed on 86 breast cancer biopsies and 50 available matched baseline cancer-free whole blood samples from the same individuals, selected from a cohort of middle-aged women in Sweden. To determine whether the mutations can be detected in blood plasma prior to cancer diagnosis, we further designed a nested case-control study (n = 663) and validated the shortlisted mutations using droplet digital PCR. Results We detected different mutation landscapes between biopsies and matched whole blood samples. Compared to whole blood samples, mtDNA from biopsies had higher heteroplasmic mutations in the D-loop region (P = 0.02), RNR2 (P = 0.005), COX1 (P = 0.037) and CYTB (P = 0.006). Furthermore, the germline mtDNA mutations had higher heteroplasmy level than the lost (P = 0.002) and de novo mutations (P = 0.04). The nonsynonymous to synonymous substitution ratio (dN/dS) was higher for the heteroplasmic mutations (P = 7.25 × 10−12) than that for the homoplasmic mutations, but the de novo (P = 0.06) and lost mutations (P = 0.03) had lower dN/dS than the germline mutations. Interestingly, we found that the critical regions for mitochondrial transcription: MT-HSP1 (odds ratio [OR]: 21.41), MT-TFH (OR: 7.70) and MT-TAS2 (OR: 3.62), had significantly higher heteroplasmic mutations than the rest of the D-loop sub-regions. Finally, we found that the presence of mt.16093T > C mutation increases 67% risk of developing breast cancer. Conclusions Our findings show that mitochondrial genetic landscape changes during cancer pathogenesis and positive selection of mtDNA heteroplasmic mutations in breast cancer. Most importantly, the mitochondrial mutations identified in biopsies can be traced back in matched plasma samples and could potentially be used as early breast cancer diagnostic biomarkers.

Abstract Background Abdominal bracing is a maneuver widely used by rehabilitation specialists and sports trainers to improve spinal stability. This study aimed to investigate how lifting tasks with and without abdominal bracing affect the respiratory function of the diaphragm. Methods M-mode ultrasonographic assessment of diaphragmatic motion combined with spirometry was performed on 31 healthy adults. Participants were asked to breathe continuously whilst lifting a load with spontaneous abdominal muscle contraction (natural loaded breathing) and abdominal bracing (AB loaded breathing). Results Pearson’s correlations revealed strong correlations between ultrasonography and spirometry measures (p

Abstract Backround We wanted to characterize conditional survival in prostate cancer (PC) in Sweden around and after 2005 when the vast increase in incidence due to the opportunistic testing for prostate specific antigen (PSA) culminated. We hypothesize that analyzing survival data during that time period may help interpret survival trends. We focus on stage‐specific analysis using conditional survival in order to define the periods when deaths most commonly occurred. Methods Data on PC patients were obtained from the Swedish cancer registry for analysis of 1‐, 2.5‐ and 5‐year relative survival and conditional relative survival between years 2004 and 2018. Tumor‐node‐metastatic stage classification at diagnosis was used to specify survival. Results Small improvements were observed in stage‐ and age‐related relative survival duriring the study period. Applying conditional relative survival showed that survival in stage T3 up to 2.5 years was better than survival between years 2.5 and 5. Survival in stage T4 was approximately equal in the first and the subsequent 2.5‐year period. For M1, the first 2.5 year survival period was worse than the subsequent one. The proportion of high risk and M1 disease in old patients (80+ years) remained very high and their survival improved only modestly. Conclusions The data indicate that M1 metastases kill more patients in the first 2.5 years than between years 2.5 and 5 after diagnosis; T4 deaths are equal in the two periods, and in T3 mortality in the first 2.5‐year period is lower than between years 2.5 and 5 after diagnosis. Conditional survival could be applied to explore critical survival periods even past 5 years after diagnoses and to monitor success in novel diagnostic and treatment practices. Improvement of survival in elderly patients may require clinical input.

Abstract INTRODUCTION Depression is a risk factor and possible prodromal symptom of Alzheimer's disease (AD), but little is known about subsequent risk of developing depression in persons with AD. METHODS National matched cohort study was conducted of all 129,410 persons diagnosed with AD and 390,088 with all‐cause dementia during 1998–2017 in Sweden, and 3,900,880 age‐ and sex‐matched controls without dementia, who had no prior depression. Cox regression was used to compute hazard ratios (HRs) for major depression through 2018. RESULTS Cumulative incidence of major depression was 13% in persons with AD and 3% in controls. Adjusting for sociodemographic factors and comorbidities, risk of major depression was greater than two‐fold higher in women with AD (HR, 2.21; 95% confidence interval [CI], 2.11–2.32) or men with AD (2.68; 2.52–2.85), compared with controls. Similar results were found for all‐cause dementia. DISCUSSION Persons diagnosed with AD or related dementias need close follow‐up for timely detection and treatment of depression. Highlights In a large cohort, women and men with AD had >2‐fold subsequent risk of depression. Risks were highest in the first year (>3‐fold) but remained elevated ≥3 years later. Risk of depression was highest in persons aged ≥85 years at AD diagnosis. Persons with AD need close follow‐up for detection and treatment of depression.

Background Little is known about risks of hypertensive disorders of pregnancy in both first‐ and second‐generation immigrant women in Europe and other Western countries; such knowledge may help elucidate the influence of genetic versus social factors on such risks. We aimed to study both first‐ and second‐generation immigrant women for the presence of all types of hypertension (preexisting hypertension, gestational hypertension, preeclampsia, and eclampsia) during pregnancy. Methods and Results A cohort study was conducted using data derived from the Swedish National Birth Register, the National Patient Register, and the Total Population Register. We used Cox regression analysis to compute hazard ratios (HRs) and 99% CIs while adjusting for sociodemographic factors and comorbidities. The first‐generation study included a total of 1 084 212 deliveries and 68 311 hypertension cases, and the second‐generation study included 989 986 deliveries and 67 505 hypertension cases. The fully adjusted HR (with 99% CI) for hypertension in pregnancy among first‐generation immigrant women was 0.69 (0.66–0.72), and among second‐generation immigrant women, it was 0.88 (0.86–0.91), compared with Swedish‐born women with 2 Swedish‐born parents. Women born in Finland or with parent(s) from Finland had higher risks, with fully adjusted HRs (99% CIs) of 1.30 (1.18–1.43) and 1.12 (1.07–1.17), respectively. Conclusions Both first‐ and second‐generation immigrant women had overall lower risks of hypertension in pregnancy compared with other Swedish women. However, the risk reduction was less pronounced in second‐generation compared with first‐generation immigrant women, suggesting that environmental factors in Sweden may have an important influence on risk of hypertension during pregnancy.

Background Long‐term survival after single‐ventricle palliation and the effect of dominant ventricle morphology in large, unselected series of patients are scarcely reported. Methods and Results This nationwide cohort study included all children undergoing operation with single‐ventricle palliation during their first year of life in Sweden between January 1994 and December 2019. Data were obtained from institutional records and assessment of underlying cardiac anomaly and dominant ventricular morphology was based on complete review of medical records, surgical reports, and echocardiographic examinations. Data on vital status and date of death were retrieved from the Swedish Cause of Death Register, allowing for complete data on survival. Among 766 included patients, 333 patients (43.5%) were classified as having left or biventricular dominance, and 432 patients (56.4%) as having right ventricular (RV) dominance (of whom 231 patients had hypoplastic left heart syndrome). Follow‐up was 98.7% complete (10 patients emigrated). Mean follow‐up was 11.3 years (maximum, 26.7 years). Long‐term survival was significantly higher in patients with left ventricular compared with RV dominance (10‐year survival: 91.0% [95% CI, 87.3%–93.6%] versus 71.1% [95% CI, 66.4%–75.2%]). RV dominance had a significant impact on outcomes after first‐stage palliation but was also associated with impaired survival after completed total cavopulmonary connection. In total, 34 (4.4%) patients underwent heart transplantation. Of these 34 patients, 25 (73.5%) had predominant RV morphology. Conclusions This study provides clinically relevant knowledge about the long‐term prognosis in patients with different underlying cardiac anomalies undergoing single‐ventricle palliation. RV dominance had a significant impact on outcomes after initial surgical treatment but was also associated with impaired survival after completed Fontan circulation. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03356574.

BackgroundAlcohol consumption contributes to excess morbidity and mortality in part through the development of alcohol-related medical conditions (AMCs, including alcoholic cardiomyopathy, hepatitis, cirrhosis, etc.). The current study aimed to clarify the extent to which risk for these outcomes differs as a function of socioeconomic position (SEP), as discrepancies could lead to exacerbated health disparities.Methods and findingsWe used longitudinal Swedish national registries to estimate the individual and joint associations between 2 SEP indicators, educational attainment and income level, and risk of AMC based on International Classification of Diseases codes, while controlling for other sociodemographic covariates and psychiatric illness. We conducted Cox proportional hazards models in sex-stratified analyses (N = 1,162,679 females and N = 1,196,659 males), beginning observation at age 40 with follow-up through December 2018, death, or emigration. By the end of follow-up, 4,253 (0.37%) females and 11,183 (0.93%) males had received an AMC registration, corresponding to overall AMC incidence rates among females and males of 2.01 and 5.20, respectively. In sex-stratified models adjusted for birth year, marital status, region of origin, internalizing and externalizing disorder registrations, and alcohol use disorder (AUD) registration, lower educational attainment was associated with higher risk of AMC in both females (hazard ratios [HRs] = 1.40 to 2.46 for low- and mid-level educational attainment across 0 to 15 years of observation) and males (HRs = 1.13 to 1.48). Likewise, risk of AMC was increased for those with lower income levels (females: HRs = 1.10 to 5.86; males: HRs = 1.07 to 6.41). In secondary analyses, we further adjusted for aggregate familial risk of AUD by including family genetic risk scores for AUD (FGRSAUD), estimated using medical, pharmacy, and criminal registries in extended families, as covariates. While FGRSAUD were associated with risk of AMC in adjusted models (HR = 1.17 for females and HR = 1.21 for males), estimates for education and income level remained largely unchanged. Furthermore, FGRSAUD interacted with income level, but not education level, such that those at higher familial liability to AUD were more susceptible to the adverse effect of low income. Limitations of these analyses include the possibility of false negatives for psychiatric illness registrations, changes in income after age 40 that were not accounted for due to modeling restrictions, restriction to residents of a high-income country, and the inability to account for individual-level alcohol consumption using registry data.ConclusionsUsing comprehensive national registry data, these analyses demonstrate that individuals with lower levels of education and/or income are at higher risk of developing AMC. These associations persist even when accounting for a range of sociodemographic, psychiatric, and familial risk factors. Differences in risk could contribute to further health disparities, potentially warranting increased screening and prevention efforts in clinical and public health settings.

Abstract Administration of oral medicinal products as crushed tablets or open capsules is an important delivery option for patients suffering from dysphagia. To obtain full interchangeability of generics with the original products, demonstration of bioequivalence (BE) between both products administered as crushed tablets/open capsules was required for poorly soluble product by European Medicines Agency (EMA) at the time of development of our rivaroxaban and deferasirox generic products. We present the results of two BE studies with modified administration of these products, which compared relative bioavailability between generic and reference products. In the rivaroxaban study, the test product was administered as a capsule sprinkled on and mixed with applesauce, whereas the reference tablet was crushed and administered with applesauce under fed conditions. In the deferasirox study, both treatments were administered as crushed tablets under fasting conditions. Both studies applied a two‐way crossover design and were conducted after a single‐dose in healthy volunteers. The 90% confidence interval of the geometric mean ratio area under the analyte concentration versus time curve, from time zero to the time of the last measurable analyte concentration and maximum measured analyte concentration over the sampling period of the test to reference ratio were 103.36–110.37% and 97.98–108.45% for rivaroxaban, respectively, and 96.69–107.29% and 94.19–109.45% for deferasirox, respectively. Thus, the BE criteria (80.00–125.00%) were met in both studies which demonstrated that bioavailability was not affected when the test and reference products were administered in the form of crushed tablet/open capsule. These results support the argument of redundancy of crushed product studies for poorly soluble drugs, which is in line with the currently revised position of the EMA on this topic.

BackgroundOvarian cancer ranks 12th in cancer incidence among women in the United States and 5th among causes of cancer-related death. The typical treatment of ovarian cancer focuses on disease management, with little attention given to the survivorship needs of the patient. Qualitative work alludes to a gap in survivorship care; yet, evidence is lacking to support the delivery of survivorship care for individuals living with ovarian cancer. We developed the POSTCare survivorship platform with input from survivors of ovarian cancer and care partners as a means of delivering patient-centered survivorship care. This process is framed by the chronic care model and relevant behavioral theory. ObjectiveThe overall goal of this study is to test processes of care that support quality of life (QOL) in survivorship. The specific aims are threefold: first, to test the efficacy of the POSTCare platform in supporting QOL, reducing depressive symptom burden, and reducing recurrence worry. In our second aim, we will examine factors that mediate the effect of the intervention. Our final aim focuses on understanding aspects of care platform design and delivery that may affect the potential for dissemination. MethodsWe will enroll 120 survivors of ovarian cancer in a randomized controlled trial and collect data at 12 and 24 weeks. Each participant will be randomized to either the POSTCare platform or the standard of care process for survivorship. Our population will be derived from 3 clinics in Texas; each participant will have received some combination of treatment modalities; continued maintenance therapy is not exclusionary. ResultsWe will examine the impact of the POSTCare-O platform on QOL at 12 weeks after intervention as the primary end point. We will look at secondary outcomes, including depressive symptom burden, recurrence anxiety, and physical symptom burden. We will identify mediators important to the impact of the intervention to inform revisions of the intervention for subsequent studies. Data collection was initiated in November 2023 and will continue for approximately 2 years. We expect results from this study to be published in early 2026. ConclusionsThis study will contribute to the body of survivorship science by testing a flexible platform for survivorship care delivery adapted for the specific survivorship needs of patients with ovarian cancer. The completion of this project will contribute to the growing body of science to guide survivorship care for persons living with cancer. Trial RegistrationClinicalTrials.gov NCT05752448; https://clinicaltrials.gov/study/NCT05752448 International Registered Report Identifier (IRRID)PRR1-10.2196/48069

Abstract Background Low serum cobalamin concentrations have been associated with ileal malabsorption in dogs with chronic enteropathy. Increased serum methylmalonic acid (MMA) concentrations indicate cobalamin deficiency on a cellular level. Few studies have evaluated serum cobalamin concentrations or methylmalonic acid concentrations in juvenile dogs with parvoviral enteritis or nonparvoviral acute enteropathies. Objectives Evaluate serum cobalamin and methylmalonic acid concentrations in juvenile dogs (6 weeks to 10 months old) with parvoviral enteritis or nonparvoviral acute enteropathy. Animals Thirty‐one juvenile dogs with parvoviral enteritis, 29 dogs with nonparvoviral acute diarrhea (NPVAD), and 40 healthy juvenile control dogs. Methods Single‐center, prospective, observational, cross‐sectional study. Serum cobalamin and, when sufficient serum was available, MMA concentrations were measured. Results Most serum cobalamin concentrations were within the adult reference interval. Serum cobalamin concentrations in healthy dogs (median, 848 ng/L; range, 293‐1912 ng/L) were significantly higher than in dogs with parvoviral enteritis (P = .0002; median, 463 ng/L; range,

Lung cancer is a leading cause of cancer deaths worldwide. The aim of this study was to investigate heavy metal(loid)s (Cd, Pb, Hg, Cr, Mn, Mo, Ni, and As) in lung cancer patients in order to elucidate their role as lung cancer environmental risk factors. Sixty-three patients of both sexes with adenocarcinoma stage IIIB or IV were enrolled in this research. The heavy metal(loid) urine concentrations were measured using ICP-MS. Arsenic was quantified above 10 μg/L in 44.44% of the samples. Nickel urinary concentrations above the ToxGuide reference levels were found in 50.79% of the samples, while lead was quantified in 9.52% of the urine samples. The urinary chromium levels were above the mean ToxGuide levels in 41.27% of the patients and were significantly higher in men in comparison with women (p = 0.035). The chromium urinary concentrations were positively associated with the CRP serum levels (p = 0.037). Cadmium was quantified in 61.90% of the samples with levels significantly higher in females than in males (p = 0.023), which was associated with smoking habits. Mercury was measured above the limit of quantification in 63.49% of the samples and was not associated with amalgam dental fillings. However, the Hg urinary concentrations were correlated positively with the ALT (p = 0.02), AST (p < 0.001), and GGT (p < 0.001) serum levels. In 46.03% of the samples, the Mo concentrations were above 32 μg/L, the mean value for healthy adults according to the ToxGuide, and 9.52% of the patients had Mn levels higher than 8 μg/L, the reference value for healthy adults based on ToxGuide data. The obtained results are preliminary, and further studies are needed to have a deeper insight into metal(loid) exposure’s association with lung cancer development, progression, and survival prediction.

We report the discovery and characterization of a small planet, TOI-1408 c, on a 2.2 day orbit located interior to a previously known hot Jupiter, TOI-1408 b ( P = 4.42 days, M = 1.86 ± 0.02 M _Jup , R = 2.4 ± 0.5 R _Jup ) that exhibits grazing transits. The two planets are near 2:1 period commensurability, resulting in significant transit timing variations (TTVs) for both planets and transit duration variations for the inner planet. The TTV amplitude for TOI-1408 c is 15% of the planet’s orbital period, marking the largest TTV amplitude relative to the orbital period measured to date. Photodynamical modeling of ground-based radial velocity (RV) observations and transit light curves obtained with the Transiting Exoplanet Survey Satellite and ground-based facilities leads to an inner planet radius of 2.22 ± 0.06 R _⊕ and mass of 7.6 ± 0.2 M _⊕ that locates the planet into the sub-Neptune regime. The proximity to the 2:1 period commensurability leads to the libration of the resonant argument of the inner planet. The RV measurements support the existence of a third body with an orbital period of several thousand days. This discovery places the system among the rare systems featuring a hot Jupiter accompanied by an inner low-mass planet.

Lumbar intrathecal administration provides an ideal route for drug delivery into the central nervous system, especially when dorsal root ganglions are the main target for the therapy in rat model of chronic pain. Two main methods of lumbar intrathecal administrations are chronic catheter implantation and the acute needle puncture. Chronic catheter implantation involves surgical manipulation to insert micro indwelling catheter into the intrathecal space. However, this method is invasive, produces inflammatory reactions, and generates more surgical stress. Acute needle puncture is less invasive and cheaper however is technically challenging to perform. We performed an ultrasound-guided lumbar intrathecal injection in six male Sprague Dawley rat cadavers, on average weighing 250-300 grams. Fresh rat cadavers were positioned in a sternal recumbent position, vertebrae were palpated and scanned using a linear probe ultrasound. A 25G needle insertion was advanced with real-time ultrasound guidance, and placement was confirmed prior to dye injection (Methylene blue, Sigma Aldrich). Cadavers were then dissected, and the vertebrae were visually inspected for dye staining. All three cadavers that underwent intrathecal injection with sagittal and axial plane ultrasound guidance showed positive dye staining within the intrathecal space, confirming successful acute intrathecal administration. There was one successful intrathecal injection under sagittal plane-only ultrasound guidance. Ultrasound is a useful, operator-dependent tool to guide acute needle puncture intrathecal administration.

Summary: Background: Drug repurposing provides a cost-effective approach to address the need for breast cancer prevention and therapeutics. We aimed to identify actionable druggable targets using Mendelian randomization (MR) and then validate the candidate drugs using population-based analyses. Methods: We identified genetic instruments for 1406 actionable targets of approved non-oncological drugs based on gene expression, DNA methylation, and protein expression quantitative trait loci (eQTL, mQTL, and pQTL, respectively). Genome-wide association study (GWAS) summary statistics were obtained from the Breast Cancer Association Consortium (122,977 cases, 105,974 controls). We further conducted a nested case–control study using data retrieved from Swedish registers to validate the candidate drugs that were identified from MR analyses. Findings: We identified six significant MR associations with gene expression levels (TUBB, MDM2, CSK, ULK3, MC1R and KCNN4) and two significant associations with gene methylation levels across 21 CpG islands (RPS23 and MAPT). Results from the nested case–control study showed that the use of raloxifene (targeting MAPT) was associated with 35% reduced breast cancer risk (odds ratio, OR, 0.65; 95% confidence interval, CI, 0.51–0.83). However, usage of estradiol, tolterodine, and nitrofurantoin (also targeting MAPT) was associated with increased breast cancer risk, with adjusted ORs and 95% CI of 1.10 (1.07–1.13), 1.16 (1.09–1.24), and 1.09 (1.05–1.13), respectively. The effect of raloxifene and nitrofurantoin lost significance in further validation analyses using active-comparator and new-user design. Interpretation: This large-scale MR analysis, combined with population-based validation, identified eight druggable target genes for breast cancer and suggested that raloxifene is an effective chemoprevention against breast cancer. Funding: Swedish Research Council, Cancerfonden, Crafoordska Stiftelsen, Allmänna Sjukhusets i Malmö Stiftelsen för bekämpande av cancer, 111 Project and MAS cancer.

ABSTRACTBackground: There are two primary phenotypic models of comorbidity between post-traumatic stress disorder (PTSD) and drug use disorder (DUD), i.e. self-medication (PTSD precedes and causes DUD) and susceptibility (DUD precedes and causes PTSD). We sought to clarify the longitudinal relationship between PTSD and DUD, while examining sex differences.Method: We used approximately 23 years of longitudinal data from Swedish population registries to conduct two complementary statistical models: Cox proportional hazard models (N ≈ 1.5 million) and a cross-lagged panel model (N ≈ 3.8 million).Results: Cox proportional hazards models, adjusting for cohort and socioeconomic status, found strong evidence for the self-medication hypothesis, as PTSD predicted increased risk for DUD among both women [hazard ratio (HR) = 5.34, 95% confidence interval (CI) 5.18, 5.51] and men (HR = 3.65, 95% CI 3.54, 3.77), and moreover, that the PTSD to DUD association was significantly higher among women (interaction term 0.68, 95% CI 0.65, 0.71). The results of the susceptibility model were significant, but not as strong as the self-medication model. DUD predicted risk for PTSD among both women (HR = 2.43, 95% CI 2.38, 2.50) and men (HR = 2.55, 95% CI 2.50, 2.60), and HR was significantly higher in men (interaction term 1.05, 95% CI 1.02, 1.08). Investigating the pathways simultaneously in the cross-lagged model yielded support for both pathways of risk. The cross-paths instantiating the susceptibility model (0.10–0.22 in females, 0.12–0.19 in males) were mostly larger than those capturing the self-medication model (0.01–0.16 in females, 0.04–0.22 in males).Conclusions: We demonstrate that the relationship between PTSD and DUD is bidirectional, with evidence that future research should prioritize examining specific pathways of risk that may differ between men and women.

Abstract To examine the risk of post-polio syndrome (PPS) in immigrant groups using native Swedish-born individuals as referents. This is a retrospective study. The study population included all individuals aged 18 years and older registered in Sweden. PPS was defined as having at least one registered diagnosis in the Swedish National Patient Register. The incidence of post-polio in different immigrant groups, using Swedish-born individuals as referents, was assessed by Cox regression, with hazard ratios (HRs) and 99% confidence intervals (CI). The models were stratified by sex and adjusted for age, geographical residence in Sweden, educational level, marital status, co-morbidities, and neighbourhood socioeconomic status. In total 5300 post-polio cases were registered, 2413 males and 2887 females. Fully adjusted HRs (99% CI) in immigrants versus Swedish-born were 1.77 in men (1.52–2.07) and 1.39 (1.19–1.62) in women. Statistically significant excess risks of post-polio were found in the following subgroups: men and women from Africa, HRs (with 99% CI) 7.40 (5.17–10.59) and 8.39 (5.44–12.95), respectively, and Asia, HRs 6.32 (5.11–7.81) and 4.36 (3.38–5.62) respectively, and in men from Latin America, HR 3.66 (2.17–6.18). It is of importance to be aware of risks of PPS in immigrants settled in Western countries, and that it is more common in immigrants from regions of the world where polio is still prevalent. Patients with PPS need treatment and proper follow-up until polio has been eradicated through global vaccination programs.

Abstract Aims This study aims to determine the familial incidence of dilated (DCM) and hypertrophic cardiomyopathy (HCM) in first‐degree, second‐degree, and third‐degree relatives of affected individuals. Methods and results In this population‐based multigenerational cohort study, full‐siblings, half‐siblings, and cousin pairs born to Swedish parents between 1932 and 2015 were included, and register‐based DCM and HCM diagnoses among relatives were ascertained. Adjusted odds ratios (ORs) for DCM and HCM were calculated for relatives of individuals with DCM and HCM compared with relatives of individuals without DCM and HCM for reference. Total study population included 6 334 979 subjects and consisted of 5 577 449 full‐siblings, 1 321 414 half‐siblings, and 3 952 137 cousins. Overall, 10 272 (0.16%) unique individuals were diagnosed with DCM and 3769 (0.06%) with HCM. Of these, 7716 (75.12%) and 2375 (63.01%) were males, respectively. Familial risk ORs for DCM were 5.35 [95% confidence intervals (CI): 4.85–5.90] for full‐siblings, 2.68 (95% CI:1.86–3.87) for half‐siblings, and 1.72 (95% CI:1.12–2.64) for cousins of affected individuals. The ORs for HCM were 42.44 (95% CI:37.66–47.82) for full‐siblings, 32.70 (95% CI:21.32–50.15) for half‐siblings, and 36.96 (95% CI:29.50–46.31) for cousins of affected individuals. In sex‐stratified analysis, relatives of affected females were found more likely to be affected than were relatives of affected males, with stronger aggregation observed for HCM. Conclusions Familial risk of HCM and DCM is high and associated with genetic resemblance, with strongest aggregations observed in relatives of affected females with HCM, whereas this association was distinctly attenuated for DCM. The finding of a Carter effect, more pronounced in HCM, suggests a multifactorial threshold model of inheritance.